Great discoveries in neuroscience hold promise for reducing the burden of many of the most disabling conditions that threaten human health on a global scale, including mental illnesses and addictions. Increasingly, exceptionally innovative science inspires hope that these devastating brain-based disorders may be prevented, treated, and even cured but, as the BRAIN 2025 Scientific Vision notes, a suite of novel ethical challenges confronts those engaged in innovative neuroscience. These concerns include the deepest questions about what defines humanity and personhood, what forms of novel inquiry may exceed ethically acceptable limits in society, and how to perform ethically sound studies with volunteers who may be vulnerable to exploitation in the research situation. Such issues are particularly salient in mental illness and addiction research because these conditions affect cognition, emotion, motivation, behavior, and self-governance of potential participants. Importantly, some of these ethical issues are amenable to empirical study, which can yield valuable insights and evidence-informed practices that strengthen and enable ethically sound human brain investigation. The overarching goal of this proposal is thus to accelerate neuroscience toward lessening the burden of mental illness and addiction through hypothesis-driven empirical ethics inquiry in three parts. First, we determine the distinct ethical issues and problems encountered in innovative neuroscience related to mental illness and addiction through semi-structured interviews with neuroscientists, neuroethicists, and institutional review board members. Informed by our past work and grounded in a rigorous conceptual model, we examine factors both negative and positive that influence research decisionmaking by people with mental illness and addiction in the context of innovative neuroscience research, and compare their decisionmaking with that of individuals with diabetes and healthy controls. Finally, we develop a new, low-burden screening tool to tailor and enhance the safeguard of informed consent in brain research, providing investigators with a practical, actionable, and protocol-adaptable method for strengthening positive-valence factors and ameliorate negative-valence factors affecting participant decisionmaking. Maximizing our established record of expertise in empirical ethics investigations and neuroethics, this sequence of projects leverages access to the exceptional neuroscience research conducted at Stanford University, including work by BRAIN initiative investigators; provides extensive, systematically collected data on influences on decisionmaking about innovative neuroscience research participation by individuals with mental or physical illness and healthy controls; and develops a new evidence-informed tool for use as a best practice in safeguarding human volunteers in cutting-edge neuroscience.